Method of manufacturing penicillin



Jan. 2, 1951 METHOD OF MANUFACTURING PENICILLIN Filed Feb. 21, 1946 #950 arc.

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INVENTORS GEORGE H. BROWN 8: RUDOLPH A. BIERWIRTH Arrae/vsy Patented Jan. 2, 1951 UNITED STATES PATENT OFFICE ma'rnon or MANUFACTURING ramcmnm Brown and Rudolph a. Bierwirth,

Georgell.

Princeton, N. 1., a'ssignors to Radio Corporation of America, a corporation of Delaware Application February :1, 1946, Serial No. 649,296

Our present invention relates to the .manufac tureoftheraredrugpenicillinandhasforits principal object to provide a simple and reliable method of manufacturing crystalline penicillin. 'I'hereareseveralwaysofderivingthedrug penicillin from its mother liquor. By way of example, the mother liquor, or a chemically abstracted concentrate thereof, ma be dehydrated by the so called "f Reichel U. S. (Reissue 20,989) or by the electric can" field 'method d in our now abandoned than say. 50 F.),.and hence must be kept under refrigeration Y We have new discovered that under certain conditions, later specified, it is commercially practical to produce penicillin in crystalline form and thatthedruginthisformmaybestoredformany weeks at temperatures as high as 100 F. without any appreciable loss in its potency.

As above indicated our invention is in the nature of a "discovery and, in fact, was predicateduponouriointobservationthatintesting.

penicillin which had been dried in the "electronic centrifuge described in Bierwirths application Ser. No. 557,053, and now Patent No. 2,512,004, certain finished lots of the drug exhibited a much longer shelf-life and to heatthanotherlotsmadebythesamemethod from the same batch of mother liquor. We then observed the difference in the physical structure of the elemental particles of the different lots and learned that the superior product was, invariably, crntalline, and the other product amorhous. We have since empirically. the several factors which determine the ultimate form of the drug and have formulated the following procedure for selectively achieving the crystalline and the amorphous forms thereof.

Wehavefoundthatifthecrystallineformis to be achieved it is tlal that the mother be spread in a relatively thin film during the drying operation. This can be don most convenmethod? (see 4 China. (Cl. 15H) iently by subjecting an oversized receptacle containing a predetermined quantity of the liquor to centrifugal force so-that it is spread in a. uniformly thin film over the inner surface of the v receptacle. We then subject the film of liquid to a relatively low pressure (say, one which will sustain a column of the order of 5 to mm. of mercury) and to a temperature no higher than about65 F. until its moisture content comprises less'than 5 percent and preferably no more than 4, percent, by weight, of the film. The moisture contentis quite critical; that is to say, if the material is removed from the drier at a time when the moisture content of the film is 5 percent or more, the resulting product will comprise an amorphous solid; whereas if its fluid content is 4 percent or less it will be crystalline in form.

0 In either event, the moisture content of the drug may befurther reduced, either with radio ire-- quency energy or in a. conventional drying oven,

vordinary temperatures (i. e. temperatures higher 25 without altering the characteristics of its elemental particles. If the mother liquor is dried,

ab initio, without spreading the liquid, the drug will assume the amorphous form.

Although we are not certain of th reasons for 7 crystal formation under one set of conditionspnd non-crystallization under the others, we have determined that after the 4 percent (approximate) moisture-content level is reached the amount of moisture remaining in the liquor is no longer able to influence the ultimate form of the drug. We therefore believe that crystallization takes place at or about the 4 percent moisture level.

Having regard to the high degree of solubility of the active ingredient of the drug it appears that the liquor at the said 4 percent moisturelevel comprises a super-saturated solution; therefore, to achieve the crystalline form it is necessary that the ori inal dilute solution be converted into a super-saturated solution at some point during the drying cycle. In any event, we have determined that adjacent to the 4 percent moisture-level it is essential to maintain conditions which favor the very rapid production of solid nuclei, and that these conditions are present when theliquor is spread in the form of a relatively thin film so that it presents a large surface of evaporation.

The figure of the drawing is a view partly in" section of an apparatus that can be used in carrying out the method described.

The conditions which favor very rapid proliquonorarelativelydiluteconcenhationthereoi', duction of solid nuclei are further enhanced peratureof85til orless.

when radio frequency energy is employed as the source of heat. Accordingly, in carrying our invention into eii'ect we prefer to employ an electronic centrifuge. such, for example, as the one shown in the accompanying drawing, wherein l designates an evacuable chamber containing a motor driven spindle 3 which supports a glass bottle I for rotation about its vertical axis between two capacitor electrodes I and 9 which will beunderstoodtobeenergizedbyasuitablesource ll of high frequency current. As dwcrihed by Bierwirth in his copending application Ber. No. 557,053 the source ll may conveniently comprise a 2 kilowatt 30 megacycle oscillator. V

In applying our invention to the manufacture of crystalline penicillin we prefer to start with a solution of the mother liquor in the concentra- 1 V the ipercent moisture-level is, substantially .number of cubic centimeters in the original solution; Thus, 2 cubic centimeters of a liquid. io'fqthe original concentration. will reach the4 percent level in approximately minutes; Another rapid but accurate checkas to whether the product is in crystalline form t to observe whether or not the film remaim on thewallsoithc'receptaclewhenthespinninghas stopped; ii-it doesremain, the product is crystallinegif'it-fiows phous.- a.

Inthecommercialpracticeofourinventionit ispreferablednthe interestsofeconommtokeep theliquidinthecentrifugeonlysolongasisreoifthesaidsurfaceitisamor- 'quired to achieve the 4percent moisturedevel and to complete the drying operation in a conven- 4 which comprhea spreading a predetermined quantityofpenicillinliquorintoathinfllm,di-

electricallyheatingsaidthinfilminalowiarem sureahnaspheretoatemperature no higherthan F.foranumberof minutes substantialiyequal to 5 timu the nlnnber of cubic centimeters in said predetermined quantity of penicillin liquor.

2.11 method of making crntalline penicillin which comprhes spreading a predetermined quantity of penicillin liquor into a thin film. dielectrically heating said thin film in a low pres- 'sureatmosphereofnomorethantiomillimeters ofmercurytoatemperaturenohigherthan 65 1!. for a number of minutes substantially equal to five times the number of cubic centimeters in said predetermined quantity of penicillin liquor, whereby the liquid content of said film comprises substantially no more than four percentbyweisht. andthen desiccating said film.

3.1lieinventionassetforthinclaim1and whereinsaidthinfihnisformedhysubjecting said liquor to centrifugal force.

4. 'lheinventionassetforthinclaim1,whereinsaidlowpressureatmcsphereisoitheorder of fivemillimeters of mercury.

v GDORGBILBROWN.

RUDOLPH A. BIERWIRTH.

REFERENCES CITED vso Thefoliowingreferencesareofrecordinthe file oi this patent:

UNITED STATES PATENTS Number Name Date 1342M Kinssbury Oct. 9, 1917 1,539,140 Schneible Mar. 1'7, 1925 2,234,166 Hickman Mar. 11. 1941 2,308,00l Hickman Jan. 12, 1943 2,360,108 Christie Oct. 10. 1944 O'I'HER REFERENCES Chemical and lnaineerlngiNews, vol. 23, #16, All!- 25, 1.45, p. 1450. r

Chemical A86. Feb. 9. 1948, pp. 157-181.

'about5miliimetersofmercuryandapiatetem Whatweclaimis:

I Solution-Prom proceedings of the Institute of nadiolngineeral'eb. 1946.

Stability d Penicillin-in Aqueous Solutions, JnBact. vol. 49, Jan. 1945 (pp. 85. 94, 

1. A METHOD OF MAKING CRYSTALLINE PENICILLIN WHICH COMPRISES SPREADING A PREDETERMINED QUANTITY OF PENICILLIN LIQUOR INTO A THIN FILM, DIELECTRICALLY HEATING SAID THIN FILM IN A LOW PRESSURE ATMOSPHERE TO A TEMPERATURE NO HIGHER THAN 65* F. FOR A NUMBER OF MINUTES SUBSTANTIALLY EQUAL TO 5 TIMES THE NUMBER OF CUBIC CENTIMETERS IN SAID PREDETERMINED QUANTITY OF PENICILLIN LIQUOR. 